The purpose of this program project is to study the mechanisms of action of several drugs of abuse at multiple levels of the organism. These levels include the molecular, cellular, physiological/anatomical and behavioral, and the drugs studied include opioids, caffeine, and cocaine. While some of the individual projects are dedicated to elucidating in further detail the classical effects of these drugs, other projects seek to define and characterize novel effects, such as may be exerted on the immune system and on circadian rhythms. The University of Minnesota Medical School is an ideal environment for this multidisciplinary effort to understand drug abuse, because of the broad range of interests of the participating faculty and a strong institutional commitment. All the component PI's have committed themselves to work together through this program grant, and through monthly seminars and annual retreats, thus a great deal more communication and collaboration can be developed.